During the presidency of Woodrow Wilson, Lodge advocated entrance into World War I on the side of the Entente Powers. He became Chairman of the Senate Republican Conference and Chairman of the Senate Committee on Foreign Relations, emerging as the leader of the Senate Republicans. He led the opposition to Wilson's Treaty of Versailles, proposing twelve reservations to the treaty. He most strongly objected to the provision of the treaty that required all nations to repel aggression, fearing that this would erode Congressional powers and commit the U.S. to burdensome obligations. Lodge prevailed in the treaty battle and Lodge's objections would influence the United Nations, the successor to the League of Nations. After the war, Lodge participated in the creation of the Washington Naval Treaty, which sought to prevent a naval arms race. He remained in the Senate until his death in 1924.

After traveling through Europe, Lodge returned to Harvard, and in 1876, became one of the first recipients of a Ph.D. in history and government from Harvard.[4] His dissertation dealt with the Germanic origins of Anglo-Saxon land law. His teacher and mentor during his graduate studies was Henry Adams; Lodge maintained a lifelong friendship with Adams.[5]

Lodge was easily reelected time and again but his greatest challenge came in his reelection bid in January 1911. The Democrats had made significant gains in Massachusetts and the Republicans were split between the progressive and conservative wings, with Lodge trying to mollify both sides. In a major speech before the legislature voted, Lodge took pride in his long selfless service to the state. He emphasized that he had never engaged in corruption or self-dealing. He rarely campaigned on his own behalf but now he made his case, explaining his important roles in civil service reform, maintaining the gold standard, expanding the Navy, developing policies for the Philippine Islands, and trying to restrict immigration by illiterate Europeans, as well as his support for some progressive reforms. Most of all he appealed to party loyalty. Lodge was reelected by five votes.[9]

Lodge was very close to Theodore Roosevelt for both of their entire careers. However, Lodge was too conservative to accept Roosevelt's attacks on the judiciary in 1910, and his call for the initiative, referendum, and recall. Lodge stood silent when Roosevelt broke with the party and ran as a third-party candidate in 1912. Lodge voted for Taft instead of Roosevelt; after Woodrow Wilson won the election the Lodge-Roosevelt friendship resumed.[10]

Lodge was a strong backer of U.S. intervention in Cuba in 1898, arguing that it was the moral responsibility of the United States to do so:

Of the sympathies of the American people, generous, liberty-loving, I have no question. They are with the Cubans in their struggle for freedom. I believe our people would welcome any action on the part of the United States to put an end to the terrible state of things existing there. We can stop it. We can stop it peacefully. We can stop it, in my judgment, by pursuing a proper diplomacy and offering our good offices. Let it once be understood that we mean to stop the horrible state of things in Cuba and it will be stopped. The great power of the United States, if it is once invoked and uplifted, is capable of greater things than that.

Following American victory in the Spanish–American War, Lodge came to represent the imperialist faction of the Senate, those who called for the annexation of the Philippines. Lodge maintained that the United States needed to have a strong navy and be more involved in foreign affairs.

Lodge was a vocal proponent of immigration restrictions, for a number of reasons. In the late 19th and early 20th centuries, large numbers of immigrants, primarily from Eastern and Southern Europe, were flooding into industrial centers. Lodge feared that unskilled foreign labor was undermining the standard of living for American workers, and that a mass influx of uneducated immigrants would result in social conflict and national decline.

His position was also influenced by his beliefs about race. In a May 1891 article on Italian immigration, Lodge expressed his concern that immigration by "the races who have peopled the United States" was declining, while "the immigration of people removed from us in race and blood" was on the rise.[14] He considered northern Italians superior to southern Italians, not only because they tended to be better educated, but because they were more "Teutonic" than their southern counterparts, whose immigration he sought to restrict.[15][16]

Lodge was a supporter of "100% Americanism," a common theme in the nativist movement of the era. In an address to the New England Society of Brooklyn in 1888, Lodge stated:

Let every man honor and love the land of his birth and the race from which he springs and keep their memory green. It is a pious and honorable duty. But let us have done with British-Americans and Irish-Americans and German-Americans, and so on, and all be Americans ... If a man is going to be an American at all let him be so without any qualifying adjectives; and if he is going to be something else, let him drop the word American from his personal description.[17]

He did not believe, however, that all races were equally capable or worthy of being assimilated. In "The Great Peril of Unrestricted Immigration" he wrote that "you can take a Hindoo and give him the highest education the world can afford ... but you cannot make him an Englishman", and cautioned against the mixing of "higher" and "lower" races:

On the moral qualities of the English-speaking race, therefore, rest our history, our victories, and all our future. There is only one way in which you can lower those qualities or weaken those characteristics, and that is by breeding them out. If a lower race mixes with a higher in sufficient numbers, history teaches us that the lower race will prevail.[18]

As the public voice of the Immigration Restriction League, Lodge argued in support of literacy tests for incoming immigrants. The tests would be designed to exclude members of those races he deemed "most alien to the body of the American people."[19] He proposed that the United States should temporarily shut out all further entries, particularly persons of low education or skill, the more efficiently to assimilate the millions who had come. From 1907 to 1911, he served on the Dillingham Commission, a joint congressional committee established to study the era's immigration patterns and make recommendations to Congress based on its findings. The Commission's recommendations led to the Immigration Act of 1917.

Lodge was a staunch advocate of entering World War I on the side of the Allied Powers, attacking President Woodrow Wilson for poor military preparedness and accusing pacifists of undermining American patriotism. After the United States entered the war, Lodge continued to attack Wilson as hopelessly idealistic, assailing Wilson's Fourteen Points as unrealistic and weak. He contended that Germany needed to be militarily and economically crushed and saddled with harsh penalties so that it could never again be a threat to the stability of Europe. However, apart from policy differences, even before the end of Wilson's first term and well before America's entry into the Great War, Lodge confided to Teddy Roosevelt, "I never expected to hate anyone in politics with the hatred I feel toward Wilson."[20]

The summit of Lodge's Senate career came in 1919, when as the unofficial Senate majority leader, he dealt with the Treaty of Versailles. He wanted to join the League of Nations with reservations. The Democrats in the Senate, following Wilson's direction, rejected Lodge's proposal to join the League with reservations. Republicans opposed joining under Wilson's terms of no reservations which meant the League could force the U.S. to enter a war without approval of Congress. In the end the U.S. never joined the League of Nations.[22] Lodge won in the long run—his reservations were incorporated into the United Nations in 1945, where the U.S. was given a veto.[23]

Lodge's key objection to the League of Nations was Article X. It required all signatory nations to repel aggression of any kind if ordered to do so by the League. Lodge rejected an open-ended commitment regardless of relevance to the national security interests of the United States. He especially insisted that Congress must approve. Lodge was also motivated by political concerns; he strongly disliked President Wilson[24] and was eager to find an issue for the Republican Party to run on in the presidential election of 1920.

Senator Lodge argued for a powerful American role in world affairs:

The United States is the world's best hope, but if you fetter her in the interests and quarrels of other nations, if you tangle her in the intrigues of Europe, you will destroy her powerful good, and endanger her very existence. Leave her to march freely through the centuries to come, as in the years that have gone. Strong, generous, and confident, she has nobly served mankind. Beware how you trifle with your marvelous inheritance; this great land of ordered liberty. For if we stumble and fall, freedom and civilization everywhere will go down in ruin.[25]

Lodge appealed to the patriotism of American citizens by objecting to what he saw as the weakening of national sovereignty: "I have loved but one flag and I can not share that devotion and give affection to the mongrel banner invented for a league."

The Senate was divided into a "crazy-quilt" of positions on the Versailles question.[26] It proved possible to build a majority coalition, but impossible to build a two thirds coalition that was needed to pass a treaty.[27] One block of Democrats strongly supported the Versailles Treaty. A second group of Democrats supported the Treaty but followed Wilson in opposing any amendments or reservations. The largest bloc, led by Lodge, comprised a majority of the Republicans. They wanted a Treaty with reservations, especially on Article X, which involved the power of the League of Nations to make war without a vote by the United States Congress. Finally, a bi-partisan group of 13 "irreconcilables" opposed a treaty in any form. The closest the Treaty came to passage was in mid-November 1919, when Lodge and his Republicans formed a coalition with the pro-Treaty Democrats, and were close to a two-thirds majority for a Treaty with reservations, but Wilson rejected this compromise. Cooper and Bailey suggest that Wilson's stroke on September 25, 1919, had so altered his personality that he was unable to effectively negotiate with Lodge. Cooper says the psychological effects of a stroke were profound: "Wilson's emotions were unbalanced, and his judgment was warped. ... Worse, his denial of illness and limitations was starting to border on delusion."[28]

The Treaty of Versailles went into effect but the United States did not sign it, and made separate peace with Germany and Austria-Hungary. The League of Nations went into operation, but the United States never joined. Historians agree that the League was ineffective in dealing with major issues, but they debate whether American membership would have made much difference.[29] In 1945 it was replaced by the United Nations, which assumed many of the League's procedures and peacekeeping functions, although Article X of the League of Nations was notably absent from the UN mandate. That is, the UN was structured in accordance with Lodge's plan, with the United States having a veto power in the UN which it did not have in the old League of Nations. Henry Cabot Lodge Jr., Lodge's grandson, served as U.S. Ambassador to the United Nations from 1953 to 1960.

Henry Cabot Lodge was one of the best informed statesmen of his time, he was an excellent parliamentarian, and he brought to bear on foreign questions a mind that was at once razor sharp and devoid of much of the moral cant that was so typical of the age. ... [Yet] Lodge never made the contributions he should have made, largely because of Lodge the person. He was opportunistic, selfish, jealous, condescending, supercilious, and could never resist calling his opponent's spade a dirty shovel. Small wonder that except for Roosevelt and Root, most of his colleagues of both parties disliked him, and many distrusted him.[31]

Lodge served on the Board of Regents of the Smithsonian Institution for many years. His first appointment was in 1890, as a Member of the House of Representatives, and he served until his election as a senator in 1893. He was reappointed to the Board in 1905 and served until he died in 1924. The other Regents considered Lodge to be a "distinguished colleague, whose keen, constructive interest in the affairs of the Institution led him to place his broad knowledge and large experience at its service at all times."[32]

Grenville, John A. S. and George Berkeley Young. Politics, Strategy, and American Diplomacy: Studies in Foreign Policy, 1873-1917 (1966) pp 201–238 on "The Expansionist: The education of Henry Cabot Lodge"

Hewes, James E. Jr. (August 20, 1970). "Henry Cabot Lodge and the League of Nations". Proceedings of the American Philosophical Society. American Philosophical Society. 114 (4): 245–255.